Parkinson's disease (PD), a debilitating neurodegenerative disorder characterized by the progressive death of dopaminergic neurons in the substantia nigra, is increasingly recognized as having a complex multi-factorial etiology. Vitamin D, which is produced in the body principally in response to sunlight exposure, influences numerous biological processes, and has been investigated for its potential role in diseases such as multiple sclerosis (as an immune modulator), and some cancers (as an anti-oxidant). Evidence from a number of laboratory studies demonstrates that vitamin D acts as a neuroprotective agent in toxin-induced and genetic models of PD, and studies in humans suggest geographic differences in PD rates exist with north-south gradients. Whether inadequate sunlight exposure leading to deficient production of vitamin D is associated with PD, however, has not been adequately investigated to date in human populations. The goal of the proposed research is to generate pilot data investigating a potential novel mechanism of pathogenesis for sporadic PD;specifically, we will examine the hypothesis that long-term low levels of vitamin D either through inadequate sunlight exposure or alterations in metabolic genes that influence physiological vitamin D levels increase the risk of PD. We will utilize the unique existing resource created by our group at UCLA over the past decade in the NIEHS-funded Parkinson Environment Gene (PEG) study (368 cases, 401 population controls). In the PEG study, we have 1) access to a sophisticated and validated GIS model of UV exposure which we will apply to residential history of PEG subjects to generate individual estimates of cumulative lifetime and average annual UV radiation exposure, and 2) stored DNA samples with which we will assess polymorphisms and haplotype patterns in vitamin D pathway genes. We will test associations between long- term UV exposure measures and PD using multivariable logistic regression models adjusted for potential confounding factors such as age, race, gender, education, smoking, dietary sources of vitamin D, skin pigmentation and pesticide exposure. Similarly, we will examine whether genetic variations presumed to result in different physiological vitamin D activity in genes critical to the vitamin D pathway (VDR, GC, CYP27A1, CYP27B1 and CYP24A1) increase the risk of PD. We will also preliminarily investigate gene-gene and gene- environment interactions to assess whether the estimated effects of sunlight exposure and hence circulating vitamin D metabolite levels on PD are modified by variants in the above genes, as well as whether the selected genes interact with each other to increase or decrease PD risk. The proposed research will thus explore a novel mechanism in the etiology of PD and generate pilot data that - if successful - we plan to replicate in a larger Danish sample (4000 cases and controls) with comparatively less sun exposure than the PEG Central California population. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is a debilitating neurodegenerative disorder that affects approximately 55,000 adults in the US each year. Environmental factors, human genetic variation, and gene-environment interactions likely contribute to PD. We will explore a novel hypothesis that long-term low levels of vitamin D either through inadequate sunlight exposure or alterations in genes that influence vitamin D levels increase the risk of PD. If successful, this research could have important implications for future recommendations in PD prevention.